The five hundred species of cone snails produce small, conformationally constrained peptides in their venoms which generally target receptors and ion channels in the nervous system. The many tens-of- thousands of different Conus peptides are generated by only a few superfamilies, and are organized within each venom into groups of peptides which act synergistically for a common physiological objective. One general goal of this program is the continuing identification and characterization of Conus peptides which target novel receptor and ion channel subtypes. However, another major goal is to understand the underlying principles of molecular recognition and drug development that the cone snails have evolved. The program is organized into a venom resource core, a peptide chemistry core and an electrophysiological core. These cores also directly support "discovery cores" that are exploratory and/or collaborative on Conus peptides which are not directly supported as projects. Three major projects comprise the program. The goal of the first project is to understand the underlying design of Conus peptides that allow them to discriminate between closely related target receptors. The standard features of Conus peptides which confer target selectively will be identified. The second project focuses on a few fish-hunting Conus venoms; the goal is to understand in mechanistic detail how efficient prey capture is achieved by elucidating the role of each individual Conus peptide, and evaluating the synergy between groups of peptides. Finally, the third project investigates the genetic basis of Conus peptide hypervariability, and in addition characterize the enzymatic basis of an unusual post-translational modification, the gamma-carboxylation of glutamate residues.